Immunology of Autoimmunity

Question 1

when do autoimmune diseases occur

Answer 1

when components of the human immune system become perturbed
- some factors involved in this are known

Question 2

how do biologics used to treat autoimmune diseases work

Answer 2

1. work by interacting and modulating with components of the innate and adaptive immune system
   - so autoimmune diseases can be treated by either dampening down these adaptive immune responses (mostly auto reactive B and T cells)
   - or innate responses (mostly proinflammatory cytokines)
2. based on antibodies- work by blocking receptors or binding to and inactivating their ligands

Question 3

what do many autoimmune diseases manifest as

Answer 3

chronic inflammatory diseases

Question 4

what are the characteristics of innate immunity

Answer 4

• present at all times
• reacts immediately
• activates the adaptive system

Question 5

what are the characteristics of adaptive immunity

Answer 5

• develops in response to infection and is protective against specific pathogens
• leverages components of the innate response and develops memory
• both innate and adaptive are required for normal function

Question 6

what is inflammation

Answer 6

the reaction of vascularised living tissue to local injury
- it is a series of vascular and cellular reactions, aiming to protect the body against the injurious agent

Question 7

what are the cardinal signs of inflammation

Answer 7

1. heat
2. redness
3. swelling
4. pain
5. loss of function

Question 8

what are the types of inflammation

Answer 8

1. acute- sudden onset and short duration
2. chronic- gradual onset and long duration

Question 9

give examples of innate immune cells

Answer 9

1. neutrophils
2. macrophages
3. dendritic cells
4. natural killer cells

Question 10

where are monocytes derived

Answer 10

derived from hematopoietic stem cells in bone marrow
- blood= 1-6% leukocyte

Question 11

what is the function of monocytes

Answer 11

1. migrate into tissues and differentiate into macrophages
2. they phagocytose microorganisms and present antigens to T cells

Question 12

what does the name of monocyte derived cells depend on

Answer 12

depends on the tissue they reside in:
1. liver= Kupffer cells
2. lung- alveolar Mf
3. CNS- microglial cells
4. bone- osteoclasts

Question 13

where are polymorphonuclear neutrophils derived

Answer 13

• 50-70% of circulating white blood cells
• infection activates cytokines that stimulate the bone marrow to produce neutrophils

Question 14

what is the function of neutrophils

Answer 14

1. they are active phagocytic cells
2. they circulate in peripheral blood for 7-10 hours and migrate by extravasation into tissues, where they have a lifespan of a few days
3. they are attracted to tissues by chemotactic factors

Question 15

give examples of soluble mediators

Answer 15

cytokines and chemokines

Question 16

how does the balance and level of cytokines and chemokines secreted affect the outcome of the response

Answer 16

1. alert to infection
2. recruit cells to site
3. activate further immune response

Question 17

what effect do cytokines have on endothelial cells

Answer 17

change the morphology, adhesive properties and permeability of endothelial cells

Question 18

give examples of cytokines

Answer 18

IL1, IL6, TNFa

Question 19

describe the permeability of post endothelial cells

Answer 19

impermeable to cells and plasma

Question 20

what is autoimmunity

Answer 20

the responses to self antigens or antigens associated with the microbiota that leads to tissue damage and disease

Question 21

when does autoimmunity occur

Answer 21

when adaptive cells break self tolerance
-host cells recognised as foreign and adaptive immune cells target them for destruction

Question 22

how is auto inflammation caused

Answer 22

when innate immune cells become activated
- due to dysregulated secretion of pro inflammatory cytokines and consequent damage to host tissues

Question 23

what is the critical function of the immune system

Answer 23

to discriminate self from non self

Question 24

what do autoimmune responses resemble

Answer 24

resemble normal immune responses to pathogens, in that T and B lymphocytes are activated by antigens (autoantigens)

Question 25

describe the result of the effects of autoantigens

Answer 25

1. gives rise to auto reactive effector (T) cells and autoantibodies (from B cells) against the self antigen 2. regulatory T cells may also fail to do their job of keeping the immune system in line 3. such dysregulated immune responses to self tissues lead to chronic syndromes - autoimmune diseases

Question 26

what is CD4 lineage

Answer 26

antigen presenting cells see antigen which present it as peptides with MHC II to naive CD4+ T helper cells, which become effector T cells of 4 basic types

Question 27

where does CD4 lineage occur

Answer 27

in the adaptive immune system

Question 28

how does a lymphocyte distinguish between self and non self

Answer 28

1. there are mechanisms that prevent autoimmunity like checkpoints - each partially effective in preventing anti self responses - together, acts synergistically to prevent autoimmunity without ablating protection against pathogens 2. ultimate aim is immunological tolerance

Question 29

what is immunological tolerance

Answer 29

mechanisms hat prevent an immune response being mounted against the bodys own tissues - this is manifested by immunological non reactivity of B and T cells to self antigens

Question 30

what are the 2 major groups of checkpoints

Answer 30

1. central tolerance mechanisms in thymus and bone marrow 2. peripheral tolerance mechanisms in secondary lymphoid tissue/sites of inflammation

Question 31

what are the functions of T regulatory cells

Answer 31

1. protectors against autoimmunity 2. express a transcription factor which alters the expression of many genes 3. when activated, Tregs express large quantities of the cytokines TGFB and IL10 - these are immunosuppressants that inhibit activity of NK cells and CD8 cells 4. Tregs also have powerful destructive effects on APCs such as dendritic cells 5. the antigenic peptides recognised by the TCRs of Tregs tend to be self peptides (autoantigens) 6. so major function is to inhibit CD4+ Tn1, Tn2, Tn17, CD8 and CTLs from mounting an immune attack against self components to protect the body against autoimmunity

Question 32

what occurs when there is a lack of Tregs

Answer 32

severe autoimmune conditions arise

Question 33

what does inflammation due to hashimotos disease lead to

Answer 33

leads to underactive thyroid gland

Question 34

what is the diagnostic sign of Hashimotos disease

Answer 34

enlarged thyroid

Question 35

what are symptoms of Hashimotos disease

Answer 35

1. enlarged thyroid 2. front of neck looks swollen 3. may make swallowing difficult 4. weight gain 5. fatigue 6. paleness/puffiness in face 7. joint/muscle pain 8. constipation 9. hair loss or thinning 10. slowed heart rate

Question 36

what is the treatment of HD

Answer 36

daily use of synthetic thyroid hormone - levothyroxine

Question 37

what does RA show characteristics of

Answer 37

both autoimmune and auto inflammatory disease

Question 38

describe the autoinflammatory responses in RA

Answer 38

1. once RA is triggered, immune cells migrate into joints where they produce large quantities of immune mediators (cytokines/chemokines), leading to activation and recruitment of more immune cells into the tissue

Question 39

what do mutations in cells of the innate immune system lead to

Answer 39

1. leads to elevated levels of proinflammatory cytokines, creating a positive feedback loop of exacerbating inflammation - by blocking these secreted cytokines, the systemic inflammatory symptoms are alleviated

Question 40

why were immunotherapies developed and what do they do

Answer 40

1. were developed to decrease the amount of circulating TNFa, IL6 and IL1B 2. these drugs (tocilizumab, etanercept) are able to bind to and sequester these cytokines or their receptors

Question 41

what is the mode of action of TNFa, IL1 and IL6

Answer 41

binding of an inflammatory cytokine to its receptor leads to the production of inflammatory effector molecules

Question 42

what is TNFa involved in

Answer 42

involved in systemic inflammation - as TNF promotes the proinflammatory response, amplified and dysregulated production of TNF if associated with autoimmune disorders such as RA, ankylosing spondylitis, IBS and psoriasis - these disorders can be treated using a TNF inhibitor

Question 43

what is TNFa secreted by

Answer 43

macrophages

Question 44

what is the role of IL6

Answer 44

1. regulates many pathways that could contribute to its effect on inflammatory disease progression 2. during CD4 T cell differentiation, IL6 promotes IL17 and IL21 production and suppresses Treg cell function 3. IL6 promotes neutrophil and macrophage recruitment and survival through induction of IL17 production 4. also acts on non immune cells, altering the function of fibroblasts and osteoclasts 5. this all leads to deposition of matrix, antibody complexes and proteases in the targeted tissue, leading to tissue destruction